Epidemiological data has demonstrated that colon cancer is disproportional in incidence and mortality between Caucasians and African Americans (AA). Whereas socioeconomic and dietary differences contribute to this disparity other underlying factors must be involved. For instance, the response to chemopreventive agents is different between these two populations. Since chemopreventive agents exert their effect through a molecular target, this disparity would suggest differences at the genetic level. Therefore, the generation and evaluation of chemopreventive agents that address the issue of chemo-resistance is essential. A promising colon cancer chemopreventive agent, phospho-sulindac (P-S), inhibits colon cancer cell growth more potently than sulindac by inhibiting cell proliferation and enhancing cell killing. However, very little is known about the molecular targets in the cancer cell that are responsible for this effect. Our hypothesis, based on preliminary results, is that miRNA expression/regulation differs between AA and Caucasians and this difference may account, at least in part, a) for the differential response to chemoprevention and b) for the differential incidence of colorectal cancer. To test these hypotheses, we propose the following three specific aims: 1) To study the effect of P-S on p53, NF-kB, 2-catenin, and cell kinetics in human colon cancer cell lines originating from Caucasians and AA; 2) To assess the effect of P- S on the miRNA profile in a p53 null murine model of colon cancer; and, 3) Determine the miRNA profile in human colon cancer samples from AA and Caucasian patients. The results from these findings will lead to the understanding of a worldwide issue and provide details for the development of chemopreventive agents that will span diverse populations.